CN116270966A - Application of polypeptide RK12 as active ingredient - Google Patents
Application of polypeptide RK12 as active ingredient Download PDFInfo
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- CN116270966A CN116270966A CN202310544989.1A CN202310544989A CN116270966A CN 116270966 A CN116270966 A CN 116270966A CN 202310544989 A CN202310544989 A CN 202310544989A CN 116270966 A CN116270966 A CN 116270966A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Inorganic Chemistry (AREA)
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- Dermatology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of biological medicine, and discloses application of polypeptide RK12 as an active ingredient, wherein bacterial cell death is caused by destroying the integrity of bacterial cells by utilizing interaction of the polypeptide RK12 and a bacterial cell wall membrane and inducing leakage of contents in cells, and meanwhile, healing of diabetic ulcer wound can be promoted, and the polypeptide RK12 has the pharmaceutical characteristics of easy synthesis and good water solubility, so that the polypeptide RK12 has good clinical application prospect in treatment of diabetic ulcers or wounds caused by combined infection.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of polypeptide RK12 serving as an active ingredient in preparing a medicament for treating diabetic foot.
Background
Diabetes mellitus (Diabetes mellitus, DM) is a metabolic disease, chronic disease characterized by hyperglycemia. Clinically DM is mainly divided into three categories: type I diabetes, type II diabetes, and gestational diabetes. About 12% -25% of type I or type II diabetics develop foot ulcers, i.e. diabetic feet (Diabetic foot ulcer, DFU). Diabetic feet are foot infections, ulcers and/or deep tissue damage caused by diabetic patients by abnormalities in the distal nerve of the lower limb and varying degrees of peripheral vascular disease. The high morbidity, infection rate, death rate and amputation rate of the medical care and health system bring heavy burden to the global medical care and health system. Foot ulcers are statistically about 910 ten thousand to 2610 ten thousand diabetics occur annually worldwide. Compared with non-diabetic foot patients, the death rate of the diabetic foot patients is increased by 2.5 times, and hospitalization cost is increased by 11 times. Patients are frequently admitted and re-diagnosed, and the quality of life is seriously affected by the problems of wound pain and the like.
The development and progression of diabetic foot ulcers is affected by a number of factors, of which peripheral neuropathy, peripheral arterial disease and local tissue infection are the most important contributors to the onset of diabetic foot ulcers. The diabetic foot is infected together on the basis of the ulcer, and common pathogenic bacteria at the ulcer of the diabetic foot are in most positive bacteria and negative bacteria and often have mixed bacteria phenomenon. About 70% of the combined DFU infections are the leading cause of amputation and mortality in diabetic patients, and diabetic foot-infected patients have a 154.5-fold risk of amputation over uninfected persons, and anti-infection is an important component in DFU treatment. Along with the long-term and large-scale application of broad-spectrum anti-drug, bacterial drug-resistant gene mutation is easy to induce, multiple drug-resistant bacteria are generated, and the difficulty of clinical treatment is increased.
The antibacterial peptide is a biological small molecular polypeptide with biological activity, the molecular weight is about 1000-7000 and Da, and the antibacterial peptide consists of 10-60 amino acid residues. The antibacterial peptide is a high-efficiency broad-spectrum antibacterial molecule which is rapidly generated by organisms after the organisms are invaded by microorganisms and participates in immune response of the organisms. Antibacterial peptides are widely available as potent defenses in the body, and thousands of antibacterial peptides have been identified from microorganisms, plants, insects, arthropods, amphibians, mammals and even humans. Antibacterial peptides act on bacteria in various ways, directly causing damage to bacterial membranes or inhibiting processes such as nucleic acid replication and translation of pathogens, and ultimately causing lysis and death of pathogenic microorganisms.
Chinese patent publication No. CN110627870a discloses a small molecular polypeptide RK12, which is a cationic antibacterial peptide, and the small molecular polypeptide RK12 has antibacterial effects on escherichia coli (a representative strain of gram-negative bacteria), candida albicans (a representative strain of fungi), staphylococcus aureus (a representative strain of gram-positive bacteria) and bacillus subtilis (a representative strain of bacillus). Patent CN110627870a discloses that RK12 has antibacterial activity against representative strains of different species of bacteria and other individual specific strains, but that the types of specific bacteria involved in infection associated with different diseases vary greatly, and does not disclose that RK12 has an effect of treating diabetic foot.
Disclosure of Invention
Accordingly, the present invention aims to provide an application of polypeptide RK12 as an active ingredient in preparing a medicament for treating diabetic foot.
In order to achieve the above purpose, the present invention provides the following technical solutions:
use of polypeptide RK12 as active ingredient for the preparation of a medicament for the treatment of diabetic foot.
Preferably, the polypeptide RK12 treats diabetic foot by promoting wound healing in diabetic patients.
In the invention, the effective dosage of the polypeptide RK12 serving as an active ingredient is preferably more than 150 mug/mL, and more preferably, the effective dosage is 200-800 mug/mL.
Preferably, the medicament is any one of a liquid preparation, a solid preparation, a semisolid preparation and a gas preparation which take the polypeptide RK12 as an active ingredient.
Preferably, the medicament is a mixture of polypeptide RK12 and sodium carboxymethylcellulose.
In the invention, the concentration of sodium carboxymethyl cellulose is preferably 0.05-0.75wt%, more preferably 0.5-wt%.
The invention has the beneficial effects that: the invention provides application of polypeptide RK12 as an active ingredient in preparing a medicament for treating diabetic foot. The antibacterial activity of the antibacterial polypeptide RK12 on different bacterial species is obviously different, and meanwhile, the antibacterial polypeptide RK12 can also promote the healing effect of ulcers and wounds of diabetic patients with combined infection, in particular to the healing effect of foot ulcers of the diabetic patients. Therefore, the method can protect host cells while eliminating pathogenic microorganisms, and has good clinical application prospect.
Drawings
In order to make the objects, technical solutions and advantageous effects of the present invention more clear, the present invention provides the following drawings for description:
figure 1 is a graph of body weight change during dosing for each group of rats.
FIG. 2 is a graph of fasting blood glucose and random blood glucose of each group of rats during the administration period (A indicates that administration was started after the model of diabetes was successfully modeled, fasting blood glucose of each group of rats was detected on days 1, 3 and 10 of administration, and B indicates that random blood glucose of each group of rats was detected on days 4, 7 and 14 of administration).
Figure 3 is a graph of wound healing for each group at 7 and 14 days of dosing.
Figure 4 is a graph showing statistics of wound healing for each of the groups at day 7 and day 14 of administration.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to limit the invention, so that those skilled in the art may better understand the invention and practice it.
Example 1
Sodium carboxymethyl cellulose (CMC-Na) is an anionic polymer compound prepared by reacting natural cellulose with caustic alkali and monochloroacetic acid, and has the advantages of no toxicity, water retention, gelation and film forming. After the small molecule polypeptide RK12 and CMC-Na are prepared into a uniform solution, CMC-Na is beneficial to maintaining the activity of the polypeptide. Therefore, the polypeptide RK12 is firstly prepared into a drug administration test solution with CMC-Na with the mass fraction of 0.5 percent. The specific method comprises the following steps: accurately weighing a proper amount of RK12 in a glass bottle by using a balance, adding CMC-Na with the mass fraction of 0.5%, and uniformly stirring until the CMC-Na is completely dissolved to prepare 200 mug/mL, 400 mug/mL and 800 mug/mL of administration test solution for later use.
In the invention, CMC-Na is used with the mass fraction of 0.05% -0.75%.
Example 2
A murine model of diabetes is constructed by selective destruction of islet beta cells by Streptozotocin (STZ), resulting in insulin deficiency. The successfully constructed diabetic model mice show pathological conditions consistent with human type I diabetes, such as hyperglycemia, polydipsia, diuresis, etc.
36 SPF-grade SD rats qualified in quarantine are selected, the rats are fasted and not forbidden for 12 hours, and the tail vein blood is taken after weighing to detect the basal blood sugar value of the rats. The animals were randomized into two groups based on body weight, 6 of which served as blank control groups and the remaining 30 served as disease model groups. The disease model group was given 1% streptozotocin solution by injection at a dose of 65 mg/kg, 10 mL/kg in volume, and the blank group was given an equivalent dose of 0.1 mmol/L sodium citrate buffer by intraperitoneal injection. After 72-h injection, each group of animals continuously takes blood for 3 days to detect blood sugar, random blood sugar and fasting blood sugar are detected, wherein 2 times of random blood sugar is higher than 16.7 mmol/L, and fasting blood sugar is higher than 11.1 mmol/L as a standard, so that the model of diabetes is determined to be successfully modeled, and the weight is weighed every day during modeling.
After the preparation of the diabetes model is completed, the model group animals are anesthetized by injecting 3% pentobarbital sodium into the abdominal cavity according to the dosage of 2 mL/kg, rectangular marks (3 mm multiplied by 7 mm) are made on the dorsum skin of the rat, the dorsum skin of the rat is taken to fascia by a puncher or a scalpel, the whole layer of skin is destroyed, and a wound surface is sterilized by a 75% alcohol cotton ball to form the defective foot skin ulcer rat model.
The test is divided into a normal control group, a model control group, a positive control group, a low, medium and high dose group of test products, and model group animals with successful modeling are randomly divided into 5 groups, namely, the model control group, the positive control group and the low, medium and high dose group of test products RK12, wherein 6 groups are respectively provided, and each group is provided with a male half and a female half, as shown in table 1.
Example 3
The dorsum of the feet of the rats in the model control group, the positive control group and the RK12 low, medium and high dose groups are taken to fascia by using a scalpel and scissors, the whole skin is destroyed, rectangular wound surfaces are formed, and the wound surface areas of animals in each group are shown in Table 2. The ulcer wound surfaces of the rats in each group are bright red, and the phenomena of blood and inflammatory pus are left and swelling are visible.
The test sets a normal control group, a model control group, a positive control group and low, medium and high dose groups of the test article RK 12. The doses of the low, medium and high dose groups of the test article RK12 are respectively 200 mug/mL, 400 mug/mL and 800 mug/mL, and the test article with corresponding doses is uniformly smeared on the wound surface once a day; the normal control group and the model group animals are given water for injection and smeared on corresponding positions and wound surfaces once daily; the positive control group was given with topical solution of aurin peptide (recombinant human epidermal growth factor) by spraying on wound surface uniformly, 1 time daily, about 4000I U/10×10 cm 2 . After administration, one layer of cellophane, two layers of gauze and non-irritating adhesive tape are used for fixing, the administration part is cleaned with warm water before the administration in the next day, and the administration is carried out according to the method every day for 14 days.
The wound healing of each group of rats was observed, and the body weight and blood glucose of the rats during the administration period were weighed and measured. And (3) photographing and recording the wound healing condition of the foot ulcer of the rat every 7 days, analyzing the Image data by adopting Image-J Image processing analysis software, and evaluating the wound healing condition. After the image is enhanced by using the color and contrast filter, selecting a red wound as a measurement area according to the difference between the red color of the wound and the background skin color, measuring the area of the wound, and calculating the wound healing rate. Wound healing rate = (original wound total area-unhealed wound area)/original wound total area 100%.
(1) Rat sign observation and body weight monitoring
Rats were observed for signs after daily dosing, and for symptoms of polydipsia, polyphagia, diuresis, weight loss, etc., were measured once on days 1 (D1), 3 (D3), 7 (D7), 10 (D10) and 13 (D13) during continuous dosing and recorded in the corresponding table 3. The rats in the disease model group showed emaciation, reduced exercise, dull hair and hair, and had symptoms of polydipsia, diuresis, weight loss, etc., and the body weights were as shown in fig. 1. The weight results show that the weight of each group of rats successfully molded does not increase or decrease.
(2) Blood sugar
The change in fasting blood glucose in rats was measured over the period of continuous dosing. During the continuous administration period of rats, each group of animals is fasted and not forbidden for more than 6 hours before blood sampling when measuring the fasting blood glucose value, tail vein blood sampling is carried out, and the fasting blood glucose value is measured by a blood glucose meter. The random blood sugar detection time is 10 am, and the specific blood sugar measurement method is the same as that of fasting blood sugar. During the test, the fasting blood glucose value (D1) of each group of animals is detected before the administration treatment after the molding, and the random blood glucose or the fasting blood glucose value of each group of animals is detected on days 3 (D3), 4 (D4), 7 (D7), 10 (D10) and 14 (D14) after the continuous administration treatment, wherein the diabetes model is based on the random blood glucose value of higher than 16.7 mmol/L and the fasting blood glucose value of higher than 11.1 mmol/L. As shown in Table 4 and FIG. 2, the average blood glucose of animals in the blank group was at normal level, but the average blood glucose of animals in the disease model group was higher than 11.1 mmol/L, indicating successful molding of hyperglycemic rats, before administration of the drug after molding. Animals in the blank control group are in normal level when RK12 is externally used for treating diabetic foot ulcers on days 3, 4, 7, 10 and 14, and the average blood sugar value of the model control group, the positive control group and the RK12 low, medium and high dose groups is higher than that of the blank control group and is in higher level.
The above results indicate that the modeling of diabetes model has been successful and that the model is stable throughout the administration period.
(3) Wound monitoring for diabetic foot ulcer of rat
On day 7 of continuous administration (D7), the model group wound developed reddish brown and yellow brown scabs, and the wound still had a layer of purulent secretion; the wound surface of the positive control group forms red brown scab and thin yellow brown scab, and the wound surface contracts; the RK12 low-dose group wound surface grows into reddish brown and thin reddish brown scab, the wound surface contracts, the RK12 low-dose group wound surface grows into reddish brown scab, and the wound surface contracts; the RK12 high dose group wound grew into red brown scab and yellow brown scab, and the wound contracted. After 14 days of continuous administration (D14), the wound surface of the model group has red scab, and part of the wound surface of the animal has yellowish thin scab; the positive control group has red brown scab on part of animal wound surface, little punctate scab, healed wound surface, and granulation on part; the RK12 low-dose group part of animal wounds have reddish brown scabs, the wounds have dander and fall off, and the part of animal wounds basically heal and leave red scars; brown scab is formed on the wound surface of partial animals in the RK12 dosage group, and red scars are reserved on the wound surface after the wound surface is basically healed; the wound surface of the RK12 high dose group is basically healed, and a small range of dark scars are left, and the result is shown in figure 3. The healing condition of the foot ulcer wound of the rat is photographed and recorded on the 7 th day and the 14 th day, the Image data is analyzed by Image-J Image processing analysis software, and the healing condition of the wound is evaluated, and the results are shown in Table 5 and FIG. 4.
The results show that the positive drug group and the polypeptide RK12 low, medium and high drug administration groups have higher wound healing rate than the model control group on days 7 and 14, and the polypeptide RK12 is the most obvious on day 7, which shows that the polypeptide RK12 has the effect of obviously promoting the healing of foot ulcer wound surface of a rat diabetes model and is equivalent to the positive drug, and the concentration is higher than 150 mug/mL.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.
Claims (7)
1. Use of polypeptide RK12 as active ingredient for the preparation of a medicament for the treatment of diabetic foot.
2. The use according to claim 1, characterized in that: the polypeptide RK12 treats diabetic foot by promoting wound healing in diabetic patients.
3. Use according to claim 1 or 2, characterized in that: the effective dosage of the polypeptide RK12 as an active ingredient is more than 150 mug/mL.
4. A use according to claim 3, characterized in that: the effective dosage of the polypeptide RK12 serving as an active ingredient is 200-800 mug/mL.
5. Use according to claim 1 or 2, characterized in that: the medicine is any one of liquid preparation, solid preparation, semisolid preparation and gas preparation which take polypeptide RK12 as an active ingredient.
6. Use according to claim 1 or 2, characterized in that: the medicine is a mixture of polypeptide RK12 and sodium carboxymethyl cellulose.
7. The use according to claim 6, characterized in that: the concentration of the sodium carboxymethyl cellulose is 0.05-0.75wt%.
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